Chiral Diamines 4:  A Computational Study of the Enantioselective Deprotonation of Boc-pyrrolidine with an Alkyllithium in the Presence of a Chiral Diamine

The enantioselective deprotonation of N-Boc-pyrrolidine (1) with i-PrLi−(−)-sparteine has been studied at theoretical levels up through B3P86/6-31G*. Four low-energy intermediate complexes involving i-PrLi−(−)-sparteine and 1 were located via geometry optimizations; two of these complexes would lead to abstraction of the pro-S hydrogen from 1, and the other two complexes would lead to loss of the pro-R hydrogen. The lowest-energy intermediate complex was found to lead to loss of the pro-S hydrogen as observed experimentally. Transition states for the deprotonations were located using the synchronous transit-guided quasi-Newton method. The calculated activation enthalpy for transfer of the pro-S hydrogen within the lowest-energy intermediate complex, 10.8 kcal/mol, is reasonable for a reaction that occurs at a relatively low temperature, and the calculated kinetic hydrogen isotope effect is in agreement with experimental data. The lower enantioselectivity observed experimentally for deprotonation of 1 using t-BuLi−(−)-sparteine is attributed to a transition-state effect due to increased steric interaction engendered by the bulky t-BuLi. Replacement of the tert-butoxycarbonyl group in 1 by a methoxycarbonyl is predicted to result in a slower deprotonation with somewhat decreased enantioselectivity. Asymmetric deprotonation of 1 using i-PrLi in combination with the C₂-symmetric diamine, (S,S)-1,2-bis(N,N-dimethylamino)cyclohexane, was calculated to be much less selective than is the deprotonation mediated by (−)-sparteine as observed experimentally. The relative energies of the intermediate complexes were fairly well-reproduced by ONIUM calculations in which the sparteine ligand less its nitrogen atoms was treated by molecular mechanics and the remainder of the complex was treated by quantum mechanics.